The basic function of an arterial blood vessel is for transportation of blood from the heart to organs and tissues of the body. When a blood vessel is diseased or becomes dysfunctional, a vascular graft is usually employed for implantation to replace or bypass the diseased or dysfunctional blood vessel. The vascular grafts include autologous blood vessel, homograft, cryo-preserved blood vessel, grafts made of synthetic material such as expanded polytetrafluoroethylene (e-PTFE) or polyester (trade name Dacron), and grafts made of biological material, such as bovine internal mammal artery, human umbilical vein, or pericardium.
A special sub-group that has dysfunctional blood vessels belongs to diabetic patients. Diabetes mellitus is characterized by a broad array of physiologic and anatomic abnormalities, for example, altered glucose disposition, hypertension, retinopathy, abnormal platelet activity, aberrations involving medium and small sized vessels, and other problems. Diabetics may depend on insulin for the prevention of ketoacidosis. Developed atrophic ulcer and infected alterations of the foot as a result of complications of diabetes mellitus may require foot amputation. The current treatment may include drug therapy, for example, U.S. Pat. No. 5,871,769 to Fleming et al. discloses methods for the prevention and/or treatment of diabetes mellitus using magnesium gluconate. However, a biocompatible vascular graft may be implanted to enhance blood circulation and eventually to salvage extremity. A vascular graft having enhanced angiogenesis capability or having angiogenesis factors may promote peripheral revascularization or neovascularization for blood perfusion so as to save the diseased foot from amputation. The process of angiogenesis (new capillary formation) is stimulated by angiogenesis factors.
The vascular graft or prosthesis made of synthetic materials is usually porous, compliant, strong, and biocompatible. The micropores of a synthetic prosthesis are believed to facilitate tissue/cells ingrowth from the host so as to accelerate the healing process. It is also suggested that the host cells tend to encapsulate a foreign substrate if the host tissue does not achieve cell infiltration into the substrate. In clinical practices, partially clotted blood, collagen, gelatin or other gelatinous material may be coated upon/into the micropores so that blood leakage during the initial phase of implantation is minimized or for future drug release purposes. U.S. Pat. No. 5,851,230 discloses a vascular graft with a heparin-containing collagen sealant, U.S. Pat. No. 6,352,710 discloses a polymerizable sealant coating that is biocompatible, tissue compliant and drug-loadable; U.S. Pat. No. 6,395,023 discloses a prosthesis coated with, a biodegradable, resorbable and biocompatible surface coating embedded with biologically active agents; all three cited patents are incorporated herein by reference.
Jayaraman et al. in U.S. Pat. Appl. Publication 2002/0065552, the entire contents of which are incorporated herein by reference, discloses coating a vascular graft with a non-porous coating to prevent short and long term fluid leakage through the pores of the vascular graft, particularly the coating being polyurethane. The Jayaraman patent is distinguishable with a proprietary Thoralon® polyether urethane urea polyurethane polymer as the coating material.
The vascular prosthesis made of biological material contains collagen as its major component. A biological prosthesis is usually crosslinked to reduce the antigenicity, enhance its antithrombogenicity, and/or improve the durability. Typical crosslinking agents include glutaraldehyde, formalin, dialdehyde starch, polyepoxy compounds or the like. For example, U.S. Pat. No. 4,082,507 discloses a treatment method with glutaraldehyde, dialdehyde starch and formalin. U.S. Pat. No. 4,806,595 discloses a treatment method with polyepoxy compounds and/or heparin. The implantation with a polyepoxy compounds treated graft usually exhibit some tissue regeneration and capillary proliferation, and may account for some degree of angiogenesis. Both patents are incorporated herein by reference.
When a vascular graft is placed in a human body, the inner walls of the graft may become lined with endothelial cells, which possess antithrombotic properties for preventing blood clotting and deposition of blood thrombus on the inner walls. In actual clinical situations, however, lining by the endothelial cells is usually much delayed, and in most cases, only the area of the anastomosis of the vascular graft becomes covered with endothelial cells while remote locations away from the anastomoses are not covered. Accordingly, thrombus continues to deposit on the inner walls where endothelialization is void. Though endothelial seeding or sodding method has been recently developed to assist the endothelialization process, the seeded/sodded cells may separate from the inner wall of a vascular graft and be washed away by the blood stream. For example, U.S. Pat. No. 4,820,626 discloses a method of treating a synthetic or naturally occurring surface with microvascular endothelial cells. One of the major drawbacks is the extra step of collecting autologous endothelial cells, enzymatic digestion by collagenase, centrifugal filtration, and seeding prior to implantation of the graft.
Furthermore, U.S. Pat. No. 5,785,965 discloses a process for sodding modified cells onto a vascular prosthesis for implantation, wherein endothelial cells derived from subcutaneous adipose tissue are genetically modified to express the endothelial cell specific angiogenic factor VEGF. The method accelerates endothelialization on the luminal surface of the vessel. However, during the early stage of transplantation, the sodded cells may separate from the inner wall of a vascular graft and be washed away by the blood stream. It was reported that when endothelial seeding is applied to grafts installed in the canine infrarenal aorta, surface thromboresistance improves significantly over controls only after the seeded grafts have healed for approximately 4 weeks. In the above discussed endothelialization processes, only autologous endothelial cells may be used because of concerns on immunological response. In almost any cell transplantation procedure, immunological response is always a concern.
Noishiki et al. in U.S. Pat. No. 5,387,236 discloses a vascular prosthesis by depositing fragments of biological tissues such as vascular tissues, connective tissues, fat tissues and muscular tissues, and cells such as vascular endothelial cells, smooth muscle cells and fibroblast cells within the wall from the inner side of a vascular prosthesis. Though the patent discloses a method for effectively depositing cells/tissues into the interstices of a vascular prosthesis mostly at adjacent the inner wall, Noishiki et al. does not disclose a method of incorporating vascular endothelial growth factor or platelet derived growth factor to promote angiogenesis and to facilitate in situ proliferation of endothelial cells and/or neovascularization inside the walls of an implanted vascular prosthesis.
Further, Noishiki in U.S. Pat. No. 5,986,168, the entire contents of which are incorporated herein by reference, discloses coating basic fibroblasts growth factor (bFGF), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PDGF), and Hepatocyte growth factor (HGF) to the inner wall of a vascular prosthesis, which is less effective for releasing the growth factors to the surrounding tissue for angiogenesis.
The angiogenesis process is believed to begin with the degradation of the basement members by proteases secreted from endothelial cells activated by mitogens such as vascular endothelial growth factor and basic fibroblast growth factor (bFGF). The cells migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space, then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane. Recent studies have applied vascular endothelial growth factor to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia.
Vascular endothelial growth factor (VEGF) is mitogenic for vascular endothelial cells and consequently is useful in promoting neovascularization (angiogenesis) and reendothelialization. Angiogenesis means the growth of new capillary blood vessels. Angiogenesis is a multi-step process involving capillary endothelial cell proliferation, migration and tissue penetration. VEGF is a growth factor having a cell-specific mitogenic activity. It would be desirable to employ a wound healing substrate incorporating a mitogenic factor having mitogenic activity that is highly specific for vascular endothelial cells following vascular graft surgery, balloon angioplasty and/or to promote collateral circulation. U.S. Pat. No. 5,194,596 discloses a method for producing VEGF while U.S. Pat. No. 6,040,157 discloses a specific VEGF-2 polypeptide. Both patents are incorporated herein by reference.
U.S. Pat. No. 5,980,887 to Isner et al. discloses a method to isolate EC (endothelial cell) progenitor from circulating blood and methods for enhancing angiogenesis with endothelial progenitor cells in a patient by administering to the patient an effective amount of an isolated endothelial progenitor cell, wherein the endothelial progenitor cell may include CD34+, flk-1− or tie-1+. However, Isner et al. in U.S. Pat. No. 5,980,887 does not disclose incorporating VEGF or EC progenitors onto a medical prosthesis for localized site-specific angiogenesis enhancement.
Hammond et al. in U.S. Pat. No. 5,880,090 discloses methods for enhancing the endothelialization of synthetic vascular grafts by administering to a graft recipient an agent that mobilizes bone marrow derived CD34+ cells into the blood stream that enhances the adherence to graft surfaces of blood-borne endothelial progenitors. Again, immunological response to any cell transplantation is generally a clinical concern and Hammond '090 patent does not disclose incorporating EC progenitors onto a medical prosthesis for localized site-specific angiogenesis enhancement.
Gordinier et al. in U.S. Pat. No. 5,599,558 discloses a method of making a platelet releasate product and methods of treating tissues with the platelet releasate. Platelet derived growth factor (PDGF) is a well-characterized dimeric glycoprotein with mitogenic and chemoattractant activity for fibroblasts, smooth muscle cells and glial cells. In the presence of PDGF, fibroblasts move into the area of tissue needing repair and are stimulated to divide in the lesion space itself. It has been reported that the cells exposed to lower PDGF concentrations are stimulated to move to environments having higher concentrations of PDGF and divide. The Gordinier et al. '558 patent is incorporated hereby by reference.
Uncontrolled over-angiogenesis or inappropriate angiogenesis is detrimental to a patient. This inappropriate angiogenesis is mostly related to non site-specific process and may result in proliferation of tumors and/or cancers. For example, it is only after many solid tumors are vascularized as a result of angiogenesis that the tumors begin to grow rapidly and metastasize. Because angiogenesis is so critical to these functions, it must be carefully regulated at any specific site or locality in order to maintain health. In some aspect of the present invention, it is provided a method for treating tumor/cancer or retinopathy with a composite implant having a site-specific angiogenesis antagonist.
A site-specific angiogenesis by incorporating VEGF, PDGF or other growth factors onto a medical material, particularly a cardiovascular device, may attract the progenitor cells, endothelial cells or the like from the circulating blood via a vascular graft to deposit onto the device surface and enhance the needed site-specific angiogenesis at the lesion site. Therefore, there is an urgent clinical need for a vascular graft having incorporated VEGF, PDGF, and the like onto the graft that may provide angiogenesis factors and circulating blood so as to enhance site-specific neovascularization and angiogenesis at the graft and its proximity to treat diabetic foot or ischemia diseases. It is another aspect of the present invention to provide an angiogenesis antagonist for inhibiting undesired angiogenesis.